The European Medicines Agency (EMA) announced on 13 April 2018 that its Pharmacovigilance Risk Assessment Committee (PRAC) has started a review of the risk of dosing errors with methotrexate medicines, used to treat cancers such as acute lymphoblastic leukaemia and various inflammatory conditions including rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis and psoriatic arthritis.
When used for inflammatory diseases, methotrexate is taken once a week, whereas for some types of cancer, the dose is higher and the medicine is used more frequently. Mistakes have led to some patients incorrectly receiving a dose every day instead of every week, with serious consequences in some cases.
Although the risk of dosing errors with methotrexate has been recognised for many years and several measures are already in place in some countries in the European Union (EU) to reduce this risk, serious adverse events related to overdosing, including fatalities, still occur.
The Spanish Agency for Medicines and Health Products, therefore, asked the PRAC to further investigate the reasons why dosing errors continue to occur in order to identify and put in place measures to prevent them.
Methotrexate can be taken orally or given by injection. Most methotrexate medicines have been authorised via national procedures. They are marketed in all EU countries under several brand names including Ledertrexate, Maxtrex, Metex and Metoject. Jylamvo (for use by mouth) and Nordimet (for injection) are the only centrally authorised medicines containing methotrexate.
The review of methotrexate has been initiated at the request of Spain, under Article 31 of Directive 2001/83/EC. The review is being carried out by the PRAC, the Committee responsible for the evaluation of safety issues for human medicines, which will make a set of recommendations. The PRAC recommendations will then be forwarded to the Committee for Medicinal Products for Human Use (CHMP), responsible for questions concerning medicines for human use, which will adopt an opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all EU Member States.
Methotrexate is authorised in the EU for two different groups of indications, each of them with a different administration schedule:
- For the treatment of cancer, such as choriocarcinoma or haematologic malignancies, requiring various frequencies of usage including daily usage.
- For the treatment of autoimmune diseases, which require immunosuppressive therapy like rheumatoid arthritis, psoriasis, Morbus Crohn and other autoimmune diseases as applicable, requiring weekly usage.
The last periodic safety update report (covering data from 1st July 2014-30th June 2017) assessed a number of adverse events related to overdose, in some cases with a fatal outcome. Furthermore, scientific publications report a significant number of adverse events associated with daily rather than weekly administration of oral methotrexate in non-oncological indications.
On 23 March, Spain notified PRAC about a referral for methotrexate oral formulations, due to serious cases, some of them fatal that have been reported following inadvertently taking the product daily instead of weekly. The PRAC further agreed during its March 2018 plenary meeting to extend the scope to also include parenteral formulations of methotrexate. For a high number of cases reported as “incorrect schedule of dose administration” the pharmaceutical form has not been reported, and a low number of cases have also been reported for parenteral formulations. In addition, the PRAC considered it necessary to perform a EudraVigilance analysis of reports of inadvertent daily instead of weekly usage of methotrexate-containing products. The data to perform this analysis will be provided by EMA and will be evaluated by PRAC together with the responses to the list of questions provided by the marketing authorisation holders (MAHs). This EudraVigilance analysis will be provided to all MAHs together with the preliminary assessment reports. The PRAC will also liaise with relevant stakeholders as part of the procedure.
The MAHs are requested to address the following questions.
An overview of the estimated patient exposure for methotrexate for marketed products in indications with once-weekly treatment courses in each EEA country, the total exposure in the EEA and worldwide exposure for the period 01.01.2013 - 31.03.2018. To calculate patient exposure by estimating the number of patients exposed based on the usual and most appropriate weekly dose and treatment duration. Patient exposure should be expressed in number of patients and patient-treatment-years. To differentiate between oral and parenteral formulation. To clearly indicate the method of calculation specifying the assumptions made for weekly dose and duration of treatment and whether the calculated patient exposure relates only to methotrexate of company or to methotrexate of all MAHs.
Each MAH should search its own database for case reports of inadvertent daily instead of weekly usage of methotrexate-containing products, including reports without adverse events for the period 01.01.2013 - 31.03.2018. The search should not be limited only to reaction field; instead, each MAH should according to its technical possibilities search in additional fields such as case narratives, other free text fields, flags, structured dosing information, etc. Whenever possible, EudraVigilance case numbers for case reports should be provided and used throughout the response document.
Based on the above the MAHs are requested to provide the following
- To provide the total number of serious cases, fatal cases, cases with an outcome of resolved with sequelae or not resolved, non-serious cases and cases without adverse events (e.g. incident, near-incident, potential errors, errors without harm, intercepted errors) in the EEA and worldwide regarding inadvertent daily instead of weekly usage. Data should also be differentiated by oral and parenteral dosage forms.
- To provide the number of reported cases stratified per products authorised for non-oncologic and oncologic indications and per products authorised only for non-oncological indications. To discuss potential differences in observed numbers. To differentiate between oral and parenteral formulation.
- To provide the number of cases of inadvertent daily instead of weekly usage per age group (children up to 12 years, adolescents up to 18 years, adults 18-64 years, patients 65-75 years, elderly over 75 years) for the whole EEA as well as stratified by country and by formulation.
- To perform a detailed root cause analysis for cases of inadvertent daily instead of weekly usage in the period 01.01.2013 - 31.03.2018 in the EEA. To provide details on the stage of medication process where the error occurred. Reference is made to available guidance in this field. To discuss whether different root causes could be related to specific characteristics of the healthcare system or patient care. To also provide information on how and who has identified the medication error. Any additional relevant information on root cause of inadvertent daily instead of weekly methotrexate usage should be provided and discussed.
- Apart from once weekly methotrexate usage, there are still alternative dosing schemes (e.g. three divided doses over 24 or 36 hours, dosing 3 days a week). To provide information on the number of cases of medication errors associated with alternative dosing schemes and discuss these cases.
- To provide information in tabular format on the daily dose used, the cumulative dose used in the period between error and event and the length of treatment prior to the error. To provide information about the management of overdose of cases with inadvertent daily instead of weekly drug usage.
To provide and discuss relevant literature on inadvertent daily instead of weekly methotrexate usage. To differentiate in the discussion between oral and parenteral formulation. Details on the search strategy should be provided.
To present the following information on the Risk Minimization Measures (RMMs) currently implemented for inadvertent daily instead of weekly usage of methotrexate: types of RMMs and dates of implementation. Dates on implementation refer to the date when a certain RMM was actually implemented by an MAH/NCA in a country (e.g. date of dissemination of DHPC, date of implementation of SmPC update recommended by PRAC, date of launch of NCA communication campaign). For presentation of data for whole EEA, only EEA-wide RMMs should be presented along with the date of the recommendation. Additionally, details of RMM activities and their effectiveness should be briefly described for each country.
To provide the information separately for oral and parenteral formulation as applicable.
Based on the review of all available data and taking into account results from root cause analyses, to provide proposals and justifications for routine and additional RMMs, which may prevent the inadvertent incorrect dosing of methotrexate products authorised in the EEA. In addition, proposals should be made on how their effectiveness could be monitored: To differentiate between oral and parenteral formulation.